Since their first clinical use with the introduction of streptomycin in 1947, the aminoglycosides (AG) have been one of the most important and widely used classes of antibiotics against most gram-negative and serious gram-positive infections. Aminoglycosides bind the A-site of the 30S ribosome, blocking bacterial protein synthesis through disruption of initiation and translation. AGs are actively transported into the bacterial cell by an energy-requiring process. Defective membrane proteins resulting from translational errors further enhance the activity of AGs by allowing passive entry of the antibiotic into the cell.
Over the past several decades of use, clinical resistance to the AGs has emerged. Aminoglycoside resistance generally occurs by one of several mechanisms, described here in order of clinical relevance:                1. Enzyme-mediated chemical modification of the drug by aminoglycoside modifying enzymes (AGME). These enzymes are carried and transferred easily by plasmids in clinical isolates and inactivate AGs by chemical modification resulting in greatly reduced ribosomal binding. Three general classes of AGME exist:                    a. N-Acetyltransferases (AAC)—catalyzes acetyl CoA-dependent acetylation of an amino group            b. O-Adenyltransferases (ANT)—catalyzes ATP-dependent adenylation of hydroxyl group            c. O-Phosphotransferases (APH)—catalyzes ATP-dependent phosphorylation of a hydroxyl group                        2. Reduced uptake or decreased cell permeability. Most typically seen in Pseudomonas aeruginosa (Pae), this form of resistance is due to a transport defect resulting in broad, intermediate level resistance to all the AGs.        3. Efflux. Drugs are pumped out of the cell before they can cause cell death. This generally results in broad resistance to all AGs. AGs are affected by both general antibiotic efflux pumps and also by AG specific pumps.        4. Altered ribosome binding sites, typically by methylation, facilitated by 16S RNA methylases. Modification at the site of aminoglycoside interaction interferes with ribosomal binding. These enzymes are also plasmid mediated.        
Coincident with the emergence of AG resistance is the rapid emergence of a variety of serious gram-negative infections, most notably hospital based (nosocomial) infections. Many of these infections are not susceptible to currently marketed and once effective antibiotics (aminoglycosides and beta-lactams) and thus pose a significant and urgent need for new or improved antibiotics. Aminoglycosides, having a long history of effective use against gram-negative infections such as Pae and Klebsiella pneumoniae (Kpn), seem well suited to address this problem if compounds can be created that effectively overcome the most clinically relevant mechanisms of AG resistance. In addition to overcoming resistance and increasing potency and spectrum, it is desirable to improve the therapeutic index, particularly by decreasing the nephrotoxicity and/or ototoxicity.